Project Summary/Abstract Epigenome-wide DNA methylation data can be combined via a weighted algorithm to index cellular age. These ?DNA methylation age? estimates can then be used to determine the extent to which an individual?s cellular age is advanced compared to his or her chronological age (i.e., accelerated cellular aging). Various environmental and behavioral factors, including trauma exposure, posttraumatic stress disorder, and poor sleep, have been associated with advanced DNA methylation age. Advanced DNA methylation age, in turn, has been linked to early onset of a number of adverse health conditions, including neurocognitive decline and metabolic aberrations. Accelerated cellular aging may help to explain the association between trauma- and stress-related psychiatric conditions and premature morbidity and mortality. However, the current state of the science in this area is limited by an almost exclusive emphasis on blood-based markers. Until now, the field has lacked systematic investigations of traumatic stress in association with advanced DNA methylation age in brain tissue and overall, little is known about the neurobiological correlates of advanced DNA methylation age. Specifically, no study has evaluated the gene expression correlates of advanced DNA methylation age in brain tissue. This project aims to address this limitation by examining associations between trauma-related psychiatric disorders (including posttraumatic stress disorder, depression, and alcohol-use disorders) and cellular age in human postmortem prefrontal brain tissue and will also evaluate the gene expression correlates of advanced DNA methylation age in the same tissue. The study will make use of an existing resource, the VA National PTSD Brian Bank, including existing DNA methylation and phenotype data, and it will also generate new expression data using the banked samples from 117 brains. We will explore associations between advanced DNA methylation age and altered expression of inflammation, immune, oxidative stress, and glucocorticoid-related genes. We will also test the novel hypothesis that advanced DNA methylation age is related to chronobiological disruption as evidenced by alterations in expression of circadian clock-related genes. The proposed study is expected to clarify the biological pathways that link traumatic stress and related psychopathology to premature aging of the brain.